PREVALENCE OF PAD IN INDIA

2. PREVALENCE OF PAD IN INDIA CUPS; n=631 Overall prevalence of PAD=3.2% PAD prevalence Normal glucose Impaired glucose Diabetes tolerance (n=517) tolerance (n=34) (n=80) 2.7% 2.9% 6.3% Prevalence of PAD in newly diagnosed subjects was 3.5% vs 7.8% in known diabetic subjects

3. PREVALENCE OF PAD IN INDIA (contd) Age group Normal glucose Glucose (yrs) tolerance intolerance 31-50 1.5% 2.1% 51-70 3.4% 6.3% >70 12.5% 17.6%

4. RISK FACTORS Older age (> 40 years) Male gender Smoking Diabetes mellitus Hyperlipidemia Hypertension Hyperhomocysteinemia When risk factors coexist, the risk increases several-fold

5. The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program demonstrated the lack of reliability of leg symptoms as the sole indicator of PAD.[1] In this study, 48% of newly diagnosed patients and 26% of previously diagnosed patients were asymptomatic (no leg pain). Another 46% of newly diagnosed patients and 62% of previously diagnosed patients presented with atypical leg symptoms. Less than 6% of newly diagnosed patients and 13% of previously diagnosed patients presented with classic Rose claudication. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001;286;1317-1324.The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program demonstrated the lack of reliability of leg symptoms as the sole indicator of PAD.[1] In this study, 48% of newly diagnosed patients and 26% of previously diagnosed patients were asymptomatic (no leg pain). Another 46% of newly diagnosed patients and 62% of previously diagnosed patients presented with atypical leg symptoms. Less than 6% of newly diagnosed patients and 13% of previously diagnosed patients presented with classic Rose claudication. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001;286;1317-1324.

6. INTERMITTENT CLAUDICATION (LEG ATTACK) Derived from the Latin word claudicatio i.e. �to limp� Caused by PAD in the lower extremities Characterized by pain, ache, cramp, tightness or sense of fatigue in leg muscles with activity Symptoms relieved by rest Results in reduced mobility and quality of life Drugs 2000; 59: 1057-1070

7. WHAT CAUSES INTERMITTENT CLAUDICATION? Atherosclerosis in peripheral arteries of legs During exercise, oxygen demand increases Muscles operate anaerobically Produce lactic acid and other metabolites Leg pain Lactic acid and other metabolites washed away on rest

8. INTERMITTENT CLAUDICATION IS INDICATIVE OF SYSTEMIC ATHEROSCLEROSIS 40-60% of patients with intermittent claudication have concomitant CAD Prevalence of cerebrovascular disease in intermittent claudication patients is 25-50% 60% of people with PAD have CAD or cerebrovascular disease or both 40% of those with coronary or cerebrovascular disease will also have PAD

9. Weitz et al summarized data on the epidemiology of lower extremity arterial disease. In the population over the age of 55, at least 5% will have intermittent claudication, leading to peripheral vascular complications and other cardiovascular morbidity and mortality. Of the patients who experience peripheral vascular complications, about 7% of patients will undergo revascularization procedures; repeat procedures will be required in approximately 26% of these patients, and major amputation will be required in 4%.[1] Patients with intermittent claudication are also at risk for other cardiovascular morbidity and mortality. In one study of this population, nonfatal cardiovascular events (MI, stroke) occurred in approximately 20% over a 5-year period. In another study, the 5-year mortality rate was estimated to be 30% (vs 10% in the appropriate control group), of which 75% were cardiovascular deaths. Weitz JI, Byrne J, Clagett P, et al. Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review. Circulation. 1996;94:3026-3049.Weitz et al summarized data on the epidemiology of lower extremity arterial disease. In the population over the age of 55, at least 5% will have intermittent claudication, leading to peripheral vascular complications and other cardiovascular morbidity and mortality. Of the patients who experience peripheral vascular complications, about 7% of patients will undergo revascularization procedures; repeat procedures will be required in approximately 26% of these patients, and major amputation will be required in 4%.[1] Patients with intermittent claudication are also at risk for other cardiovascular morbidity and mortality. In one study of this population, nonfatal cardiovascular events (MI, stroke) occurred in approximately 20% over a 5-year period. In another study, the 5-year mortality rate was estimated to be 30% (vs 10% in the appropriate control group), of which 75% were cardiovascular deaths. Weitz JI, Byrne J, Clagett P, et al. Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review. Circulation. 1996;94:3026-3049.

10. Peripheral arterial disease (PAD) often occurs with other manifestations of atherosclerosis, including cerebrovascular and cardiovascular disease. Thus, patients with PAD have an increased risk of morbidity and mortality. McKenna et al determined death rates in 744 patients who had undergone noninvasive evaluation for lower-extremity PAD. PAD was defined as an ankle-brachial index (ABI) value of ?0.85. Mortality was defined as death from ischemic heart disease, cardiovascular disease other than ischemic heart disease, cancer, and other causes.[1] This slide illustrates survival according to ABI. A clear graded relationship dependent on the level of the ABI is evident. Similar results have previously been reported. The 5-year survival for a subject with an ABI of <0.4 was only 44%, versus 90% for those with an ABI of >0.85. The relative risk for death was significantly higher than 1.00 for ABI values of <0.4 and those between 0.4 and 0.85. The relative risk for total mortality associated with PAD was 2.36 (95% CI, 1.60 to 3.48), after adjusting for baseline covariates.[1] McKenna M, Wolfson S, Kuller L. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis. 1991;87:119-128. Peripheral arterial disease (PAD) often occurs with other manifestations of atherosclerosis, including cerebrovascular and cardiovascular disease. Thus, patients with PAD have an increased risk of morbidity and mortality. McKenna et al determined death rates in 744 patients who had undergone noninvasive evaluation for lower-extremity PAD. PAD was defined as an ankle-brachial index (ABI) value of ?0.85. Mortality was defined as death from ischemic heart disease, cardiovascular disease other than ischemic heart disease, cancer, and other causes.[1] This slide illustrates survival according to ABI. A clear graded relationship dependent on the level of the ABI is evident. Similar results have previously been reported. The 5-year survival for a subject with an ABI of <0.4 was only 44%, versus 90% for those with an ABI of >0.85. The relative risk for death was significantly higher than 1.00 for ABI values of <0.4 and those between 0.4 and 0.85. The relative risk for total mortality associated with PAD was 2.36 (95% CI, 1.60 to 3.48), after adjusting for baseline covariates.[1] McKenna M, Wolfson S, Kuller L. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis. 1991;87:119-128.

11. Criqui et al previously reported that patients with large-vessel peripheral arterial disease (LV-PAD) have a high risk of cardiovascular disease�related morbidity and mortality.[1] To evaluate the relationship between the severity of PAD and cardiovascular disease-related mortality, they examined mortality data from 13 years of follow-up of their population.[2] The population consisted of residents of a free-living, predominantly white, upper-middle-class community in southern California. In total, 565 patients (256 men and 309 women) were studied. Their mean baseline age was 66 years. A battery of noninvasive measures of perfusion in the lower extremities (including segmental blood pressure and flow velocity) was used to diagnose PAD. Moderate PAD was defined as an ankle-brachial index (ABI) of 0.6 to 0.9, and severe PAD was defined as an ABI of <0.6.[2] Increases in the severity of PAD were associated with increases in mortality from cardiovascular disease. Although trends were similar in men and women, rates of death were higher in men. Subjects with isolated small-vessel PAD (ISV-PAD) also had increased mortality from cardiovascular disease compared with normal subjects.[2] Several studies have now confirmed the strong predictive value of PAD for subsequent cardiovascular-related mortality and that the risk of cardiovascular mortality increases with the severity of PAD.[2-4] Criqui MH, Langer RD, Fronek A, Feigelson HS. Coronary disease and stroke in patients with large-vessel peripheral arterial disease. Drugs. 1991;42(suppl 5):16-21. Criqui MH, Denenberg JO. The generalized nature of atherosclerosis: how peripheral arterial disease may predict adverse events from coronary artery disease. Vasc Med. 1998;3:241-245. Vogt MT, Cauley JA, Newman AB, et al. Decreased ankle/arm blood pressure index and mortality in elderly women. JAMA. 1993;270:465-469. McKenna M, Wolfson S, Kuller L. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis. 1991;87:119-128. Criqui et al previously reported that patients with large-vessel peripheral arterial disease (LV-PAD) have a high risk of cardiovascular disease�related morbidity and mortality.[1] To evaluate the relationship between the severity of PAD and cardiovascular disease-related mortality, they examined mortality data from 13 years of follow-up of their population.[2] The population consisted of residents of a free-living, predominantly white, upper-middle-class community in southern California. In total, 565 patients (256 men and 309 women) were studied. Their mean baseline age was 66 years. A battery of noninvasive measures of perfusion in the lower extremities (including segmental blood pressure and flow velocity) was used to diagnose PAD. Moderate PAD was defined as an ankle-brachial index (ABI) of 0.6 to 0.9, and severe PAD was defined as an ABI of <0.6.[2] Increases in the severity of PAD were associated with increases in mortality from cardiovascular disease. Although trends were similar in men and women, rates of death were higher in men. Subjects with isolated small-vessel PAD (ISV-PAD) also had increased mortality from cardiovascular disease compared with normal subjects.[2] Several studies have now confirmed the strong predictive value of PAD for subsequent cardiovascular-related mortality and that the risk of cardiovascular mortality increases with the severity of PAD.[2-4] Criqui MH, Langer RD, Fronek A, Feigelson HS. Coronary disease and stroke in patients with large-vessel peripheral arterial disease. Drugs. 1991;42(suppl 5):16-21. Criqui MH, Denenberg JO. The generalized nature of atherosclerosis: how peripheral arterial disease may predict adverse events from coronary artery disease. Vasc Med. 1998;3:241-245. Vogt MT, Cauley JA, Newman AB, et al. Decreased ankle/arm blood pressure index and mortality in elderly women. JAMA. 1993;270:465-469. McKenna M, Wolfson S, Kuller L. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis. 1991;87:119-128.

12. Criqui et al showed a nearly 6-fold increase in relative risk of death from cardiovascular disease in patients with large-vessel peripheral arterial disease (PAD) (average age 66 years) compared with those patients without PAD.[1] The elevated risk of death from all causes in patients with established PAD versus normal subjects was due mostly to increased rates of death from cardiovascular disease and coronary heart disease. Rates of death from other causes were not significantly elevated in PAD patients. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381-386. Criqui et al showed a nearly 6-fold increase in relative risk of death from cardiovascular disease in patients with large-vessel peripheral arterial disease (PAD) (average age 66 years) compared with those patients without PAD.[1] The elevated risk of death from all causes in patients with established PAD versus normal subjects was due mostly to increased rates of death from cardiovascular disease and coronary heart disease. Rates of death from other causes were not significantly elevated in PAD patients. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381-386.

13. The impact of peripheral arterial disease (PAD) on functional ability and quality of life were assessed in the PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program.[1] This slide shows data from two of the quality of life surveys. Patients with PAD demonstrated significantly lower scores on both the Walking Impairment Questionnaire (WIQ) and the Medical Outcome Study Short Form-36 (MOS SF-36). WIQ scores were 70 for the reference group, 49 for PAD only, and 42 for patients with PAD and CVD; this works out to PAD patients scoring 30% to 40% lower on the WIQ. Also, MOS SF-36 scores were 65 for the reference group, 53 for PAD only, and 47 for patients with PAD and CVD; this correlates to patients with PAD scoring 18% to 28% lower on the MOS SF-36. PAD patients experienced a significant decrease in health-related quality of life as compared with patients without PAD or with only CVD. Regensteiner JG, Treat-Jacobson D, Walsh ME, et al. Partners: the impact of peripheral arterial disease (PAD) on health-related quality of life (HQL). Circulation. 2000;102:II-400. Abstract 1948. The impact of peripheral arterial disease (PAD) on functional ability and quality of life were assessed in the PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program.[1] This slide shows data from two of the quality of life surveys. Patients with PAD demonstrated significantly lower scores on both the Walking Impairment Questionnaire (WIQ) and the Medical Outcome Study Short Form-36 (MOS SF-36). WIQ scores were 70 for the reference group, 49 for PAD only, and 42 for patients with PAD and CVD; this works out to PAD patients scoring 30% to 40% lower on the WIQ. Also, MOS SF-36 scores were 65 for the reference group, 53 for PAD only, and 47 for patients with PAD and CVD; this correlates to patients with PAD scoring 18% to 28% lower on the MOS SF-36. PAD patients experienced a significant decrease in health-related quality of life as compared with patients without PAD or with only CVD. Regensteiner JG, Treat-Jacobson D, Walsh ME, et al. Partners: the impact of peripheral arterial disease (PAD) on health-related quality of life (HQL). Circulation. 2000;102:II-400. Abstract 1948.

14. The impact of peripheral arterial disease (PAD) on functional ability and quality of life were assessed in the PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program.[1] All three patient groups (cardiovascular disease [CVD], PAD, or CVD + PAD) demonstrated decreased scores on the PAD QOL questionnaire when compared with the reference group. Regensteiner JG, Treat-Jacobson D, Walsh ME, et al. Partners: the impact of peripheral arterial disease (PAD) on health-related quality of life (HQL). Circulation. 2000;102:II-400. Abstract 1948. The impact of peripheral arterial disease (PAD) on functional ability and quality of life were assessed in the PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program.[1] All three patient groups (cardiovascular disease [CVD], PAD, or CVD + PAD) demonstrated decreased scores on the PAD QOL questionnaire when compared with the reference group. Regensteiner JG, Treat-Jacobson D, Walsh ME, et al. Partners: the impact of peripheral arterial disease (PAD) on health-related quality of life (HQL). Circulation. 2000;102:II-400. Abstract 1948.

15. Vascular disease can occur in multiple vascular beds, including the coronary, cerebral, and peripheral arteries, and is the underlying condition that can lead to MI, stroke, or peripheral arterial disease (PAD). These vascular conditions often coexist in patients, increasing the risk for developing ischemic events such as MI and stroke. Ness and Aronow evaluated the incidence and degree of overlap of coronary artery disease (CAD), stroke, and PAD in 1,802 elderly patients (aged ?60 years) in an academic, hospital-based geriatric practice.[1] The results demonstrated that two-thirds of patients had some manifestation of vascular disease and a significant degree of overlap of these conditions. For example, in patients with CAD, 32% of the patients had concomitant stroke, and 26% also had PAD. Ness J, Aronow WS. Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospital-based geriatrics practice. J Am Geriatr Soc. 1999;47:1255-1256. Vascular disease can occur in multiple vascular beds, including the coronary, cerebral, and peripheral arteries, and is the underlying condition that can lead to MI, stroke, or peripheral arterial disease (PAD). These vascular conditions often coexist in patients, increasing the risk for developing ischemic events such as MI and stroke. Ness and Aronow evaluated the incidence and degree of overlap of coronary artery disease (CAD), stroke, and PAD in 1,802 elderly patients (aged ?60 years) in an academic, hospital-based geriatric practice.[1] The results demonstrated that two-thirds of patients had some manifestation of vascular disease and a significant degree of overlap of these conditions. For example, in patients with CAD, 32% of the patients had concomitant stroke, and 26% also had PAD. Ness J, Aronow WS. Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospital-based geriatrics practice. J Am Geriatr Soc. 1999;47:1255-1256.

16. Patients with evidence of additional ischemia are at an even greater cross-risk of MI and stroke. Additional ischemia puts all three patient types (recent MI, recent stroke, established PAD) at increased cross-risk of MI or stroke. Cupples and colleagues evaluated the long-term prognosis of 828 patients post MI who were enrolled in the Framingham Heart Study. They found that patients with the preexisting condition of stroke who suffered an MI were at up to 103% increased risk of a second MI. Patients with intermittent claudication (a symptom of peripheral arterial disease) were at up to 104% increased risk of a second MI.[1] Preexisting atherosclerotic conditions in patients with signs of additional ischemia including MI elevate the risk of subsequent events, ie, a second MI or a stroke.[1,2] This chart is based on epidemiological data and is not intended to provide a direct basis for comparison of risks between event categories. Data for the associated risk increase in events were taken from different sources. The increase in risk of events was based on 10-year follow-up except for risk of stroke following stroke, which measures subsequent risk per year. Cupples LA, Gagnon DR, Wong ND, Ostfeld AM, Kannel WB. Preexisting cardiovascular conditions and long-term prognosis after initial myocardial infarction: the Framingham Study. Am Heart J. 1993;125:863-872. Kannel WB. Risk factors for atherosclerotic cardiovascular outcomes in different arterial territories. J Cardiovasc Risk. 1994;1:333-339. Patients with evidence of additional ischemia are at an even greater cross-risk of MI and stroke. Additional ischemia puts all three patient types (recent MI, recent stroke, established PAD) at increased cross-risk of MI or stroke. Cupples and colleagues evaluated the long-term prognosis of 828 patients post MI who were enrolled in the Framingham Heart Study. They found that patients with the preexisting condition of stroke who suffered an MI were at up to 103% increased risk of a second MI. Patients with intermittent claudication (a symptom of peripheral arterial disease) were at up to 104% increased risk of a second MI.[1] Preexisting atherosclerotic conditions in patients with signs of additional ischemia including MI elevate the risk of subsequent events, ie, a second MI or a stroke.[1,2] This chart is based on epidemiological data and is not intended to provide a direct basis for comparison of risks between event categories. Data for the associated risk increase in events were taken from different sources. The increase in risk of events was based on 10-year follow-up except for risk of stroke following stroke, which measures subsequent risk per year. Cupples LA, Gagnon DR, Wong ND, Ostfeld AM, Kannel WB. Preexisting cardiovascular conditions and long-term prognosis after initial myocardial infarction: the Framingham Study. Am Heart J. 1993;125:863-872. Kannel WB. Risk factors for atherosclerotic cardiovascular outcomes in different arterial territories. J Cardiovasc Risk. 1994;1:333-339.

18. Note: Plavix� (clopidogrel bisulfate) is not indicated for all the conditions listed on this slide. Vascular disease is the common underlying disease process for MI, ischemia and vascular death. Acute coronary syndrome (ACS) is a classic example of the progression of vascular disease to an ischemic event. ACS (in common with ischemic stroke and critical leg ischemia) is typically caused by rupture or erosion of an atherosclerotic plaque followed by formation of a platelet-rich thrombus. Atherosclerosis is an ongoing process affecting mainly large and medium-sized arteries, which can begin in childhood and progress throughout a person�s lifetime. Stable atherosclerotic plaques may encroach on the lumen of the artery and cause chronic ischemia, resulting in (stable) angina pectoris or intermittent claudication, depending on the vascular bed affected. Unstable atherosclerotic plaques may rupture, leading to the formation of a platelet-rich thrombus that partially or completely occludes the artery and causes acute ischemic symptoms. Note: Plavix� (clopidogrel bisulfate) is not indicated for all the conditions listed on this slide. Vascular disease is the common underlying disease process for MI, ischemia and vascular death. Acute coronary syndrome (ACS) is a classic example of the progression of vascular disease to an ischemic event. ACS (in common with ischemic stroke and critical leg ischemia) is typically caused by rupture or erosion of an atherosclerotic plaque followed by formation of a platelet-rich thrombus. Atherosclerosis is an ongoing process affecting mainly large and medium-sized arteries, which can begin in childhood and progress throughout a person�s lifetime. Stable atherosclerotic plaques may encroach on the lumen of the artery and cause chronic ischemia, resulting in (stable) angina pectoris or intermittent claudication, depending on the vascular bed affected. Unstable atherosclerotic plaques may rupture, leading to the formation of a platelet-rich thrombus that partially or completely occludes the artery and causes acute ischemic symptoms.

19. PRIMARY SITES OF INVOLVEMENT Femoral & Popliteal arteries: 80-90% Tibial & Peroneal arteries: 40-50% Aorta & Iliac arteries: 30%

20. Atherosclerosis results from an extensive inflammatory and fibroproliferative response to insults within the vasculature leading to disruption of normal homeostasis of the endothelium. The dysfunctional endothelium leads to an increase in adhesiveness and procoagulant properties of platelets. Atherosclerotic lesions form and through progression of the disease eventually become atherosclerotic plaques. Activated platelets can amplify the inflammatory response and are an important component leading to vasoconstriction. Rupture of the atherosclerotic plaque occurs in advanced stages of the disease and results in the formation of a thrombus and arterial occlusion. Atherosclerotic plaque, thrombosis, and vasoconstriction of the arteries all lead to decreased blood flow in the periphery. Ischemia may lead to painful symptoms that can be worsened as the demand of oxygen increases in response to activity such as walking. Painful symptoms at rest are signs of progressive disease. Ischemia may lead to cell death and tissue destruction. Progression of limb pain and destruction of tissue eventually leads to physical impairment. Ross R. Atherosclerosis�an inflammatory disease. N Engl J Med. 1999;340:115-126.Atherosclerosis results from an extensive inflammatory and fibroproliferative response to insults within the vasculature leading to disruption of normal homeostasis of the endothelium. The dysfunctional endothelium leads to an increase in adhesiveness and procoagulant properties of platelets. Atherosclerotic lesions form and through progression of the disease eventually become atherosclerotic plaques. Activated platelets can amplify the inflammatory response and are an important component leading to vasoconstriction. Rupture of the atherosclerotic plaque occurs in advanced stages of the disease and results in the formation of a thrombus and arterial occlusion. Atherosclerotic plaque, thrombosis, and vasoconstriction of the arteries all lead to decreased blood flow in the periphery. Ischemia may lead to painful symptoms that can be worsened as the demand of oxygen increases in response to activity such as walking. Painful symptoms at rest are signs of progressive disease. Ischemia may lead to cell death and tissue destruction. Progression of limb pain and destruction of tissue eventually leads to physical impairment. Ross R. Atherosclerosis�an inflammatory disease. N Engl J Med. 1999;340:115-126.

21. A recent review in The New England Journal of Medicine noted that more than 50% of patients with peripheral arterial disease (PAD) do not have �typical� claudication or leg ischemia at rest, but instead have leg pain on exertion associated with reduced ambulatory activity and quality of life.[1] Less than 5% to 10% of patients with PAD have critical leg ischemia (defined as ischemic pain in the distal foot, ischemic ulceration, or gangrene), and approximately one-third present with typical claudication. Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001;344:1608-1621.A recent review in The New England Journal of Medicine noted that more than 50% of patients with peripheral arterial disease (PAD) do not have �typical� claudication or leg ischemia at rest, but instead have leg pain on exertion associated with reduced ambulatory activity and quality of life.[1] Less than 5% to 10% of patients with PAD have critical leg ischemia (defined as ischemic pain in the distal foot, ischemic ulceration, or gangrene), and approximately one-third present with typical claudication. Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001;344:1608-1621.

22. HOW DOES AN INTERMITTENT CLAUDICATION PATIENT PRESENT CLINICALLY? Leg pain caused and reproduced by a certain degree of exertion Relieved by rest Not affected by body position Atherosclerotic lesions usually found in arterial segment one level above affected muscle group Calf claudication more commonly due to disease in femoral arteries and less commonly due to disease in popliteal or proximal tibial or peroneal arteries; Hip/Thigh/Buttock claudication due to aortoiliac disease

23. DIFFERENTIAL DIAGNOSIS CALF Venous occlusion Tight bursting pain / dull ache that worsens on standing and resolves with leg elevation Positional pain relief Chronic compartment syndrome Tight bursting pain Positional pain relief Nerve root compression Positional pain relief Baker�s cyst Positional pain relief

24. McDermott and colleagues compared the prevalence of typical and atypical leg symptoms among 163 patients diagnosed with peripheral arterial disease (137 with ABI <0.9 as established in a blood flow laboratory and 26 diagnosed via ABI screening in a general internal medicine practice).[1] Patients identified in a primary care setting were less likely to experience leg symptoms (53.8% reported no leg symptoms) than those identified in a blood flow laboratory (15.3% reported no symptoms). Atypical leg symptoms were more common among patients with PAD diagnosed in a laboratory (25.5%) than among patients diagnosed in a primary care setting (7.7%). The prevalence of pain at rest, an atypical symptom, was similar in both groups (30.7% of the laboratory-diagnosed group and 34.6% of the primary-practice diagnosed group). McDermott MM, Mehta S, Greenland P. Exertional leg symptoms other than intermittent claudication are common in peripheral arterial disease. Arch Intern Med. 1999;159:387-392.McDermott and colleagues compared the prevalence of typical and atypical leg symptoms among 163 patients diagnosed with peripheral arterial disease (137 with ABI <0.9 as established in a blood flow laboratory and 26 diagnosed via ABI screening in a general internal medicine practice).[1] Patients identified in a primary care setting were less likely to experience leg symptoms (53.8% reported no leg symptoms) than those identified in a blood flow laboratory (15.3% reported no symptoms). Atypical leg symptoms were more common among patients with PAD diagnosed in a laboratory (25.5%) than among patients diagnosed in a primary care setting (7.7%). The prevalence of pain at rest, an atypical symptom, was similar in both groups (30.7% of the laboratory-diagnosed group and 34.6% of the primary-practice diagnosed group). McDermott MM, Mehta S, Greenland P. Exertional leg symptoms other than intermittent claudication are common in peripheral arterial disease. Arch Intern Med. 1999;159:387-392.

25. McDermott and colleagues conducted a cross-sectional study of 460 patients with peripheral arterial disease (PAD) and 130 with no PAD to identify clinical characteristics and functional limitations associated with leg symptoms.[1] Two types of atypical exertional leg pain were described (atypical/carry on described pain that did not begin at rest and did not stop patients from walking; atypical/stop described pain that did not begin at rest but caused the patients to stop walking). As shown here, atypical symptoms were common among patients with comorbid diseases such as neuropathy, diabetes mellitus, intervertebral disk disease, and spinal stenosis. McDermott MM, Greenland P, Liu K, et al. Leg symptoms in peripheral arterial disease. Associated clinical characteristics and functional impairment. JAMA. 2001;286:1599-1606.McDermott and colleagues conducted a cross-sectional study of 460 patients with peripheral arterial disease (PAD) and 130 with no PAD to identify clinical characteristics and functional limitations associated with leg symptoms.[1] Two types of atypical exertional leg pain were described (atypical/carry on described pain that did not begin at rest and did not stop patients from walking; atypical/stop described pain that did not begin at rest but caused the patients to stop walking). As shown here, atypical symptoms were common among patients with comorbid diseases such as neuropathy, diabetes mellitus, intervertebral disk disease, and spinal stenosis. McDermott MM, Greenland P, Liu K, et al. Leg symptoms in peripheral arterial disease. Associated clinical characteristics and functional impairment. JAMA. 2001;286:1599-1606.

26. DIAGNOSIS History taking Careful examination of leg Pulse evaluation Ankle-brachial index (ABI): SBP in ankle (dorsalis pedis and posterior tibial arteries) ___________________________________ SBP in upper arm (brachial artery)

28. Ankle-Brachial Index Values and Clinical Classification Clinical Presentation Ankle-Brachial Index Normal > 0.90 Claudication 0.50-0.90 Rest pain 0.21-0.49 Tissue loss < 0.20

29. McDermott and colleagues evaluated the relationship between the ankle brachial index (ABI) and leg function in 740 patients (460 with peripheral arterial disease [PAD]).[1] They demonstrated that ABI is more closely related with leg function than intermittent claudication or other leg symptoms. Lower ABI scores were consistently associated with shorter distance walked in 6 minutes, lower accelerometer-measured activity over 7 days, poorer standing balance, slower walking velocity at usual and fast pace, and lower overall summary performance scores. McDermott MM, Greenland P, Liu K, et al. The ankle brachial index is associated with leg function and physical activity: the walking and leg circulation study. Ann Intern Med. 2002;136:873-883. McDermott and colleagues evaluated the relationship between the ankle brachial index (ABI) and leg function in 740 patients (460 with peripheral arterial disease [PAD]).[1] They demonstrated that ABI is more closely related with leg function than intermittent claudication or other leg symptoms. Lower ABI scores were consistently associated with shorter distance walked in 6 minutes, lower accelerometer-measured activity over 7 days, poorer standing balance, slower walking velocity at usual and fast pace, and lower overall summary performance scores. McDermott MM, Greenland P, Liu K, et al. The ankle brachial index is associated with leg function and physical activity: the walking and leg circulation study. Ann Intern Med. 2002;136:873-883.

30. A number of other noninvasive tests may be useful in the complete evaluation of patients with suspected peripheral arterial disease (PAD). Segmental blood pressure and pulse volume recordings may be useful for pinpointing the location of vascular lesions in the lower extremities, and are most useful in patients who have abnormal ABI scores at rest.[1] Pulse volume recording may be especially useful in diabetic patients with noncompressible arteries as it is less affected by medial calcinosis than segmental blood pressure recording. Exercise stress testing can aid the identification of PAD in ambulatory patients who have normal or borderline abnormal ABI scores at rest. Similarly, reactive hyperemia can aid the identification of PAD in nonambulatory patients; however, its clinical utility has been disputed. Lastly, continuous-wave (CW) Doppler waveforms and duplex ultrasonography can be used to provide additional information about the location and morphology of vascular lesions to help plan revascularization procedures. Rose SC. Noninvasive vascular laboratory for evaluation of peripheral arterial occlusive disease: part II�clinical applications: chronic, usually atherosclerotic, lower extremity ischemia. J Vasc Interv Radiol. 2000;11:1257-1275. A number of other noninvasive tests may be useful in the complete evaluation of patients with suspected peripheral arterial disease (PAD). Segmental blood pressure and pulse volume recordings may be useful for pinpointing the location of vascular lesions in the lower extremities, and are most useful in patients who have abnormal ABI scores at rest.[1] Pulse volume recording may be especially useful in diabetic patients with noncompressible arteries as it is less affected by medial calcinosis than segmental blood pressure recording. Exercise stress testing can aid the identification of PAD in ambulatory patients who have normal or borderline abnormal ABI scores at rest. Similarly, reactive hyperemia can aid the identification of PAD in nonambulatory patients; however, its clinical utility has been disputed. Lastly, continuous-wave (CW) Doppler waveforms and duplex ultrasonography can be used to provide additional information about the location and morphology of vascular lesions to help plan revascularization procedures. Rose SC. Noninvasive vascular laboratory for evaluation of peripheral arterial occlusive disease: part II�clinical applications: chronic, usually atherosclerotic, lower extremity ischemia. J Vasc Interv Radiol. 2000;11:1257-1275.

31. In the past, invasive vascular testing was considered the gold standard for vascular imaging and planning of revascularization procedures.[1] Images obtained using this procedure provide information about the level and severity of vascular disease. However, the utility of invasive imaging in all patients has been challenged, as duplex ultrasonography may provide adequate information for planning revascularization procedures in some patients. Collins KA, Sumpio BE. Vascular assessment. Clin Podiatr Med Surg. 2000;17:171-191. In the past, invasive vascular testing was considered the gold standard for vascular imaging and planning of revascularization procedures.[1] Images obtained using this procedure provide information about the level and severity of vascular disease. However, the utility of invasive imaging in all patients has been challenged, as duplex ultrasonography may provide adequate information for planning revascularization procedures in some patients. Collins KA, Sumpio BE. Vascular assessment. Clin Podiatr Med Surg. 2000;17:171-191.

32. The history and physical examination (pulse evaluation and careful examination of the leg) are usually sufficient to establish the diagnosis

33. WHY IS IT NECESSARY TO TREAT INTERMITTENT CLAUDICATION ? Symptoms worsen in 25% of patients Approximately 5% will require amputation within 5 years Around 5-10% have critical limb ischemia; risk of limb loss Increased risk of mortality, primarily for cardiovascular causes Am J Cardiol 2001; 87 (suppl): 3D-13D

34. IMPACT ON QUALITY OF LIFE Functional status severely impaired Gradual process of decline if symptoms are ignored Symptoms considered a normal part of aging process Leveraged �disability� Detrimental to quality of life; affects both leisure and work activities Peak exercise performance is about 50% that of age- matched controls, equivalent to moderate to severe heart failure patients Am J Cardiol 2001; 87 (suppl): 14D-18D Am J Med 2002; 112: 49-57

35. GOALS OF TREATMENT To relieve exertional symptoms and improve walking capacity To improve quality of life To reduce total mortality as well as cardiac and cerebrovascular morbidity and mortality

36. MANAGEMENT Risk factor modification Exercise therapy Antiplatelet therapy Medical therapy targeted at symptoms Revascularisation procedures

37. MODIFICATION OF RISK FACTORS Smoking cessation Diabetes control (FBG 80-120 mg/dl, PPG < 180 mg/dl, HbA1c < 7%) Dyslipidemia management (LDL < 100 mg/dl, TG < 150 mg/dl): Statins (RR 38%; 4S) Hypertension control (BP < 130/85 mmHg) Ramipril [RR 28%; HOPE (n=4051)]

38. EXERCISE PROGRAM Improves walking ability Requires motivation and personalised supervision Benefits lost if not maintained on regular basis Overall effectiveness limited

39. In a meta-analysis, Robless and colleagues combined and analyzed results from five trials that compared the effects of aspirin with those of ticlopidine, clopidogrel, or dipyridamole/aspirin combination in patients with peripheral arterial disease (PAD).[1] Patients with PAD treated with antiplatelet therapy other than aspirin experienced a 24% reduction in vascular events compared with patients receiving aspirin alone (95% CI, 0.64 to 0.91, P=0.003). Robless P, Mikhailidis DP, Stansby G. Systematic review of antiplatelet therapy for the prevention of myocardial infarction, stroke or vascular death in patients with peripheral vascular disease. Br J Surg. 2001;88:787-800. In a meta-analysis, Robless and colleagues combined and analyzed results from five trials that compared the effects of aspirin with those of ticlopidine, clopidogrel, or dipyridamole/aspirin combination in patients with peripheral arterial disease (PAD).[1] Patients with PAD treated with antiplatelet therapy other than aspirin experienced a 24% reduction in vascular events compared with patients receiving aspirin alone (95% CI, 0.64 to 0.91, P=0.003). Robless P, Mikhailidis DP, Stansby G. Systematic review of antiplatelet therapy for the prevention of myocardial infarction, stroke or vascular death in patients with peripheral vascular disease. Br J Surg. 2001;88:787-800.

40. In this study by Barradas and colleagues, blood was collected from 10 patients with a history of peripheral vascular disease (PVD) and 10 healthy subjects.[1] Platelet-rich plasma (PRP) preparation by centrifugation resulted in significantly lower platelet yields suggestive of increased platelet aggregation in patients with PVD compared to healthy subjects. In this study, ethylenediamine tetraacetic acid (EDTA) was more effective than aspirin in preventing platelet aggregation induced by the addition of adrenaline. EDTA is a potent calcium chelator/platelet aggregation inhibitor that works by dissociating the glycoprotein IIb/IIIa complex that is calcium dependent and involved in the aggregation of platelets. There was no significant difference among the effect of EDTA on platelet aggregation in patients with PVD compared to healthy subjects. However, aspirin was significantly less effective in preventing platelet aggregation in patients with PVD compared to healthy subjects (P<0.001). This result suggests that aspirin may not provide sufficient protection against platelet aggregation in patients with increased baseline platelet activity, such as those with PVD. Barradas MA, Stansby G, Hamilton G, Mikhailidis DP. Diminished platelet yield and enhanced platelet aggregability in platelet-rich plasma of peripheral vascular disease patients. Int Angiol. 1994;13:202-207.In this study by Barradas and colleagues, blood was collected from 10 patients with a history of peripheral vascular disease (PVD) and 10 healthy subjects.[1] Platelet-rich plasma (PRP) preparation by centrifugation resulted in significantly lower platelet yields suggestive of increased platelet aggregation in patients with PVD compared to healthy subjects. In this study, ethylenediamine tetraacetic acid (EDTA) was more effective than aspirin in preventing platelet aggregation induced by the addition of adrenaline. EDTA is a potent calcium chelator/platelet aggregation inhibitor that works by dissociating the glycoprotein IIb/IIIa complex that is calcium dependent and involved in the aggregation of platelets. There was no significant difference among the effect of EDTA on platelet aggregation in patients with PVD compared to healthy subjects. However, aspirin was significantly less effective in preventing platelet aggregation in patients with PVD compared to healthy subjects (P<0.001). This result suggests that aspirin may not provide sufficient protection against platelet aggregation in patients with increased baseline platelet activity, such as those with PVD. Barradas MA, Stansby G, Hamilton G, Mikhailidis DP. Diminished platelet yield and enhanced platelet aggregability in platelet-rich plasma of peripheral vascular disease patients. Int Angiol. 1994;13:202-207.

41. REVASCULARISATION PROCEDURES Incapacitating claudication Limb-threatening ischemia (pain at rest, non-healing ulcers and/or infections or gangrene) If symptoms persist despite medical therapy

42. MEDICAL THERAPY USED IN PAST FOR MANAGING INTERMITTENT CLAUDICATION SYMPTOMS Vasodilators (e.g. verapamil, isoxsuprine, cinnarizine, xanthinol nicotinate, cyclandelate) NEJM 2001; 344: 1608-1621

43. ANTIPLATELET THERAPY Aspirin Clopidogrel (CAPRIE Study)

44. FDA approved drugs for IC Pentoxifylline � 1984

45. WHAT IS THE CURRENT STATUS ON PENTOXIFYLLINE? Am J Med 2002; 112: 49-57

46. PENTOXIFYLLINE NOT RECOMMENDED FOR INTERMITTENT CLAUDICATION Inconsistent and modest benefit; non-significant increase in walking ability Not more effective than placebo in increasing walking ability or functional status Most trials small and not properly designed Study sample size and pentoxifylline response inversely correlated �Data are insufficient to support its widespread use� (Meta-analysis of pentoxifylline trials) NEJM 2001; 344: 1608-1621 Am J Cardiol 2001; 87 (suppl): 19D-27D

47. Cilostazol � an interesting drug with multiple effects Launched in 1988 in Japan for the treatment of leg ischemia and ulcers Subsequently marketed in Asia and Latin America to treat ischemic symptoms including ulcers, pain and cold sensation in chronic arterial occlusions In Argentina, cilostazol is indicated for secondary prevention of restenosis after coronary revascularization US FDA approved for IC

48. Pharmacology of Cilostazol 9 genes identified for Phosphodiesterases, PDE I-IX cAMP is degraded by PDE-III present in Vascular smooth muscle Platelets Cardiomyocytes Endothelial cells cAMP mediates platelet inhibitory, vasodilatory and vascular antiproliferative responses in vivo

49. UNIQUE MECHANISM OF ACTION Cilostazol

50. CILOSTAZOL EXERTS SIGNIFICANT ANTIPLATELET EFFECTS Inhibits platelet aggregation induced by ADP, collagen, adrenaline, arachidonic acid and thrombin More potent in suppressing platelet aggregation than aspirin or ticlopidine

51. EFFECT ON PERIPHERAL CIRCULATION Diabetic patients with PAD Skin temperature of finger and toe measured by infra-red thermography Cilostazol increased the digital skin temperature from 29.9 to 33.2?C Potent and steady vasodilatory effect on peripheral circulation

52. CILOSTAZOL INCREASES ICD AND ACD Vs Placebo

53. IMPROVES ANKLE-BRACHIAL INDEX

54. IMPROVES FUNCTIONAL ABILITY & QUALITY OF LIFE (ASSESSED BY QUESTIONNAIRES) Increase in physical component scale score (SF-36) by 2.99 points vs 0.12 points with placebo Increase in patients� perception of physical function by 8.3 points vs 2.3 points with placebo Improved bodily pain and general health parameters Increased walking speed by 20% (WIQ questionnaire) compared to no change with placebo J Vasc Surg 1998; 27: 267-275

55. CILOSTAZOL V/S. PENTOXIFYLLINE N=698 Treatment groups: Cilostazol 100 mg twice daily (n=227), Pentoxifylline 400 mg thrice daily (n=232), Placebo (n=239) Duration: 24 weeks Largest reported trial of any drug therapy for claudication till date Study >3 times the size of the largest previous study of pentoxifylline efficacy Provides an important perspective on the effectiveness of pentoxifylline

57. EFFICACY CONFIRMED BY META-ANALYSIS OF 8 TRIALS (N=2702; 12-24 WKS)

58. EFFICACY CONFIRMED BY META-ANALYSIS OF 8 TRIALS (N=2702; 12-24 WKS)

59. CILOSTAZOL AND LEG ULCERS Case series of 5 patients with lower extremity ischemic ulcers 3 patients not ideal candidates for angioplasty/bypass surgery; 2 refused invasive therapy Between 7 and 24 weeks of cilostazol therapy, ulcers healed in all 5 patients

60. CILOSTAZOL AND HAND ISCHEMIA Three cases of digital ischemia successfully treated with cilostazol Patient 1: Chronic, post-traumatic, cold, painful right fourth and fifth fingers. After 8 weeks of cilostazol therapy, fingers were warm and displayed normal perfusion Patient 2: Painful index finger ulceration. Within 4 weeks of cilostazol therapy, digital ulcers and pain resolved Patient 3: Traumatic right fifth digital arterial thrombosis. Within 4 weeks of cilostazol therapy, pain and cyanosis had resolved

61. CILOSTAZOL REDUCES NEED FOR LEG BYPASS SURGERY Meta-analysis of 94 antiplatelet (aspirin, ticlopidine, clopidogrel, cilostazol) studies; n=23000 Risk of requiring later limb bypass surgery reduced by 45%

62. NO EFFECT ON BLEEDING TIME Bleeding time (s) Total blood loss (?l) Before After Before After Aspirin 359 646** 14.5 30.2** Ticlopidine 323.3 528.7* 12.5 19.2* Cilostazol 313.3 343.3 12.4 13.4 Aspirin (330 mg/day), ticlopidine (300 mg/day) and cilostazol (200 mg/day) administered for 3 days inhibited platelet aggregation in response to ADP, collagen, adrenaline and arachidonic acid (n=10)

63. BLEEDING TIME UNAFFECTED BY ADDITION OF CILOSTAZOL TO CLOPIDOGREL-ASPIRIN REGIMEN Bleeding time (min) Baseline 4.5 Clopidogrel 10.2* Clopidogrel + Aspirin 17.4*# Clopidogrel + Aspirin + Cilostazol 19.9 (NS vs clop+asp)